Published: November 18, 2011

r 2011 American Chemical Society 20100 dx.doi.org/10.1021/ja208867g | J. Am. Chem. Soc. 2011, 133, 20100–20103

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A Catalytic Tethering Strategy: Simple Aldehydes CatalyzeIntermolecular Alkene HydroaminationsMelissa J. MacDonald,† Derek J. Schipper,† Peter J. Ng, Joseph Moran, and Andr�e M. Beauchemin*

Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10Marie Curie, Ottawa, Ontario, Canada K1N 6N5

bS Supporting Information

ABSTRACT: Herein we describe a catalytic tethering strat-egy in which simple aldehyde precatalysts enable, throughtemporary intramolecularity, room-temperature intermolecu-lar hydroamination reactivity and the synthesis of vicinaldiamines. The catalyst allows the formation of a mixed aminalfrom an allylic amine and a hydroxylamine, resulting in a facileintramolecular hydroamination event. The promising en-antioselectivities obtained with a chiral aldehyde also highlightthe potential of this catalytic tethering approach in asym-metric catalysis and demonstrate that efficient enantioinduc-tion relying only on temporary intramolecularity is possible.

Catalysis of intermolecular reactions is at the basis of chemicalreactivity. Bifunctional catalysts performing both substrate

activation and substrate preassociation—thus offsetting the nega-tive reaction entropy—are particularly effective in achieving highcatalytic activities for intermolecular reactions. In addition, thepreorganization that results from substrate preassociation usuallyleads to increased control in reactions where multiple productscan be formed (regio-, chemo-, or stereoselectivity).1 Recently,several strategies to incorporate a “preassociation domain” oncatalysts or ligands have been reported, thus allowing increasedefficiency through temporary intramolecularity.2 However, mostcatalysis still operate by performing the activation of one or bothsubstrates. In contrast, the catalysis of intermolecular reactions onlythrough temporary intramolecularity has received less attentionfrom the synthetic community.2a,3 Indeed, simple catalysts oper-ating only through this pathway are rare and achieve relativelysimple synthetic transformations,4 and efficient examples ofenantioselective catalysis have not been reported. In contrast,the inherent increased reactivity and control associated with tem-porary intramolecularity has typically been used in stepwise ap-proaches involving the formation of “temporary” tethers.5 Despitebeing applicable to a wide variety of chemical transformations,such tethering strategies are unfortunately not catalytic andgenerally involve two or three additional steps required for tetherassembly and cleavage. Catalytic variants of this reactivity arecritically needed since they would allow tethered reactivity to bepossible in one step and would avoid the inherent inefficiency andbyproduct formation that are associated with stepwise approaches.Herein we show that simple activated aldehydes display catalytictethering activity and demonstrate that such organocatalysis canlead to the formation of enantioenriched molecules throughefficient transfer of stereochemical information.

Aldehydes offer an opportunity to develop a catalytic tetheringreactivity because of their propensity to form acetals or aminals

reversibly from alcohols or amines under mild conditions. How-ever, the necessity of favoring substrate preassociation and forma-tion of the mixed tether (over unproductive homodimers) alongwith the issue of catalyst turnover have been serious obstacles toovercome for the development of a prototypical catalytic system(Figure 1). In our efforts to develop metal-free Cope-type hydro-aminations,6,7 we had noted the stark difference between theexcellent intramolecular reactivity in five-membered-ring systems7

and the forcing conditions required for limited intermolecularreactivity. Thus, we speculated that notoriously difficult intermo-lecular alkene hydroaminations could be achieved provided that amixed aminal such as I (eq 1), and thus temporary intramolecu-larity, could be accessed reversibly in the presence of a tetheringcatalyst. Herein we report that aldehyde-based organocatalystsform a temporary tether between hydroxylamines and allylicamines in situ, thus enabling room-temperature directed intermol-ecular metal-free hydroaminations (eq 1). We also demonstratethe potential of this approach in asymmetric catalysis, showing thata readily available α-chiral aldehyde catalyst leads to the synthesisof enantioenriched vicinal diamines with high stereocontrol.

Figure 1. Prototypical catalytic tethering strategy: activation onlythrough temporary intramolecularity.

Received: September 20, 2011

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Intermolecular alkene hydroamination stands out as a simpleand desirable reaction for which no general solution currentlyexists. While progress has been achieved using transition-metalcatalysts to overcome the high activation energy associated withthe addition of an N�H bond across electron-rich alkenes,8

reactions of unbiased alkenes typically require catalysis at hightemperatures and have limited synthetic applicability. Enantio-selective variants are also severely underdeveloped despite theindustrial importance of chiral amines.9 Furthermore, a conse-quence of the near-thermoneutral profile of the hydroaminationreaction and its negative entropy is that ideally the temperatureshould be as low as possible to maximize the yield and minimizereversibility.10 Surprisingly, directed or tethered intermolecularreactions are rare in the hydroamination literature.

To address this issue, we sought to validate the catalytic tether-ing strategy described above to achieve intermolecular Cope-typehydroaminations of allylic amines (eq 1). This reaction requiredthe formation of a mixed aminal intermediate (I) with selectivetethering of the hydroxylamine through the nitrogen atom (sincean O-linkage would prevent a further Cope-type hydroaminationstep). In this context, the work of Knight and co-workers11 on thereaction of nitrones with allylic amines provided strong support forthe formation of a transient hydroxylamine displaying the desiredhydroamination reactivity (Figure 2A). In this system, nitronesare used as reagents and become incorporated into the productthrough an aminal formation/hydroamination/ring-opening/ring-closing sequence. Indirectly, this work also suggested that acatalytic version (Figure 2B) would be possible provided that theformation of a cyclic intermediate such as II could be avoided (orbe reversible) and that an aldehyde precatalyst possessing thedesired ability to promote the formation of the mixed aminal andallow catalyst turnover could be identified.

Our work began with an extensive screening of aldehydes andketones that could potentially act as tethering organocatalysts [seeTable S1 in the Supporting Information (SI)].12 Representativereactivity and optimization data are presented in Table 1. In adeparture from this work, optimal reactivity was observed for

aldehydes bearing electron-withdrawing substituents (Table 1, en-tries 6 and 8). Our working hypothesis is that inductively destabi-lized aldehydes favor the formation of aminal I kinetically andthermodynamically, thus helping to offset the negative reactionentropy associatedwith formation of thismixed aminal intermediate.We were delighted to see that catalytic turnover is indeed possiblewith aldehydes containing an α-heteroatom, with α-benzyloxyace-taldehyde (A) being optimal (entries 6 and 8). Further optimizationof the conditions revealed that the reaction can be carried out atroom temperaturewith 20mol% catalyst and that both benzene andchloroform are competent solvents (see Tables S2�S4).

With the optimized reaction conditions in hand, we probedthe reaction scope, and the results are presented in Table 2. Theorganocatalytic reaction is compatible with allylamine (entry 1)as well as N-substituted allylamines (entries 2�12). Both allyland benzyl substituents are tolerated, allowing the synthesis oforthogonally protected vicinal diamines. Hydroxylamines bear-ing benzylic (entries 1�10) and aliphatic (entries 11�12)substituents are also suitable substrates. Tolerance of the sterichindrance associated with N-cyclohexylhydroxylamine (entry12) is also noteworthy. However, attempts to use this tetheringcatalyst with disubstituted allylic amines and homoallylic aminesled to minimal product formation. Typically, related intramole-cular hydroaminations proceed efficiently but require heatingat temperatures in the 60�100 �C range.7,11b Preliminary datasuggested that irreversible formation of the cyclic 1,2,5-oxadiazi-nane II (see Figure 2A) results in catalyst inhibition and limitedsubstrate scope with catalystA. Efforts to expand the scope of thistransformation are ongoing.

One of the hallmarks of successful organocatalytic activationmodes is that access to enantioenriched products is possible

Table 1. Representative Reactivity and Optimization Dataa

aConditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), alde-hyde (20 mol %), and C6H6 (1 mL) were charged into a vial and stirredat room temperature for 24 h. bDetermined using 1,4-dimethoxyben-zene as an internal standard.

Figure 2. (A) A stoichiometric system leading to hydroaminationproducts through a transient hydroxylamine (Knight and co-workers,ref 11). (B) Proposed catalytic cycle for a catalytic variant in which analdehyde is used as the tethering precatalyst (this work).

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through asymmetric catalysis.13 Encouraged by the success ofthis catalytic tethering strategy and the importance of the chiral1,2-diamine motif,14 we sought to validate this approach in thecontext of enantioselective catalysis.15 Gratifyingly, encouragingenantiomeric excess (ee) was observed in the reactions of severalsecondary allylic amines with N-benzylhydroxylamine using com-mercially available (R)-glyceraldehyde acetonide (B) as thecatalyst (Table 3, entries 1�3). Higher yields were also obtainedusing this catalyst rather than A (Table 2, entries 2�4 vs Table 3).Optimization efforts were pursued with the related, more easilyhandled catalyst C (see the SI), and improved enantioselectivitywas observed for the formation of 1d (87% ee; entry 4).Importantly, the enantioselectivities obtained for 1c and 1d(75 and 87% ee; entries 3 and 4) validate this tethering approachas an effective strategy in asymmetric catalysis. To the best of ourknowledge, this enantioselectivity is the highest obtained forintermolecular hydroaminations of unactivated alkenes by anymethod, including metal-catalyzed reactions.16,17 The observed

sense of induction is consistent with formation of the tem-porary stereocenter present in the tether via a Felkin�Anh-controlled addition of the allylamine to the chiral nitrone18 followedby efficient transposition of chirality19 through the rigid bicyclictransition state associated with Cope-type hydroaminations.7 Ef-forts to identify a highly enantioselective catalyst(s) and expand thesubstrate scope are ongoing and will be reported in due course.

Our proposed catalytic cycle (Figure 2B) first involves thecondensation of the hydroxylamine onto the aldehyde to form anitrone (this nitrone was observed by 1H NMR spectroscopy).Attack on this nitrone by the allylamine leads to an aminalintermediate that undergoes a facile intramolecular Cope-typehydroamination. The resulting charged intermediate favorsaminal cleavage to yield an iminium ion. Finally, condensationof a second molecule of hydroxylamine completes the catalyticcycle and releases the product, which is the result of a formalintermolecular hydroamination process. Current experimentsare directed at probing this mechanistic scenario, preventingcatalyst inhibition (via irreversible formation of intermediate II),and determining the rate-limiting step to allow subsequentimprovement of this catalytic system.

In conclusion, we have reported the validation of a catalytictethering strategy to achieve challenging intermolecular Cope-type hydroaminations under mild and metal-free conditions.This new paradigm in organocatalysis is also applicable inasymmetric synthesis, and this work highlights the fact thatsimple molecules such as chiral α-oxygenated aldehydes arecapable of efficiently inducing asymmetry only through tempor-ary intramolecularity. Therefore, we expect this advance willprompt the investigation and development of a broad range oftransformations using this concept.

’ASSOCIATED CONTENT

bS Supporting Information. Complete experimental proce-dures and characterization, catalyst identification and optimization

Table 2. Aldehyde-Catalyzed Intermolecular Cope-TypeHydroaminationa

aConditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), catalystA (20 mol %), and solvent (1 mL) were charged into a vial and stirredat room temperature for 24 h [except for entries 5 (48 h), 6 (96 h), 7(46 h), and 10 (29 h)]. b Isolated yields. c 1:1 mixture of diastereo-isomers. dAt 60 �C.

Table 3. Asymmetric Catalysis Using (R)-GlyceraldehydeKetals as Chiral Catalystsa

aConditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), catalyst(20 mol %), and C6H6 (1 mL) were charged into a vial and stirred atroom temperature for 24 h. b Isolated yields. cDetermined by chiralHPLC analysis (see the SI).

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data, assignment of absolute configuration, and NMR and HPLCspectra. This material is available free of charge via the Internet athttp://pubs.acs.org.

’AUTHOR INFORMATION

Corresponding Authorandre.beauchemin@uottawa.ca

Author Contributions†These authors contributed equally.

’ACKNOWLEDGMENT

This communication is dedicated to the memory of ProfessorKeith Fagnou. This work was initiated through support of anEnantioselective Synthesis Grant (sponsored by the CanadianSociety for Chemistry, AstraZeneca Canada, Boehringer Ingelheim(Canada) Ltd. and Merck Frosst Canada), and the NSERCCollaborative R&D Program. Support from the University ofOttawa, the Canadian Foundation for Innovation, the OntarioMinistry of Research and Innovation (Ontario Research Fundand Early Researcher Award to A.M.B.), NSERC (DiscoveryGrant and Discovery Accelerator Supplement to A.M.B.), andAstraZeneca is also gratefully acknowledged. Acknowledgment isalso made to the donors of The American Chemical SocietyPetroleum Research Fund for support of related research efforts.D.J.S. and J.M. thank NSERC for postgraduate scholarships.M.J.M. thanks Boehringer Ingelheim (Canada) Ltd. for a collabo-rative graduate scholarship. We also thank Marc Pesant forstimulating discussions.

’REFERENCES

(1) (a) For a review of substrate-directable chemical reactions, see:Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.(b) For a recent review of removable or catalytic directing groups, see:Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.(2) For an excellent recent review, see: (a) Tan, K. L. ACS Catal.

2011, 1, 877. For recent examples, see: (b) Bedford, R. B.; Coles, S. J.;Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112.(c) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am. Chem. Soc.2008, 130, 9210. (d) Gr€unanger, C. U.; Breit, B. Angew. Chem., Int. Ed.2008, 47, 7346. (e) Sun, X.; Worthy, A. D.; Tan, K. L. Angew. Chem., Int.Ed. 2011, 50, 8167.(3) (a) Pascal, R. Eur. J. Org. Chem. 2003, 1813. Also see: (b) Page,

M. I.; Jencks, W. P. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1678.(4) Several carbonyl compounds have been reported as catalysts

operating via hemiacetal intermediates. See: Ester hydolysis and alco-holysis: (a) Wieland, V. T.; Jaenicke, F. Justus Liebigs Ann. Chem. 1956,599, 125. (b) Wieland, V. T.; Lambert, R.; Lang, H. U.; Schramm, G.Justus Liebigs Ann. Chem. 1956, 597, 181. (c) Capon, B.; Capon, R.J. Chem. Soc., Chem. Commun. 1965, 502. (d) Hay, R.W.;Main, L.Aust. J.Chem. 1968, 21, 155. (e) Menger, F. M.; Whitesell, L. G. J. Am. Chem.Soc. 1985, 107, 707. (f) Menger, F. M.; Persichetti, R. A. J. Org. Chem.1987, 52, 3451. (g) Sammakia, T.; Hurley, T. B. J. Am. Chem. Soc. 1996,118, 8967. (h) Sammakia, T.; Hurley, T. B. J. Org. Chem. 1999, 64, 4652.(i) Sammakia, T.; Hurley, T. B. J. Org. Chem. 2000, 65, 974. Amidehydrolysis: (j) Pascal, R.; Lasperas, M.; Taillades, J.; Commeyras, A.NewJ. Chem. 1987, 11, 235. (k) Ghosh, M.; Conroy, J. L.; Seto, C. T. Angew.Chem., Int. Ed. 1999, 38, 514. Nitrile hydration: (l) Pascal, R.; Taillades,J.; Commeyras, A. Bull. Soc. Chim. Fr. II 1978, 3�4, 177. (m) Pascal, R.;Taillades, J.; Commeyras, A. Tetrahedron 1978, 34, 2275. (n) Pascal, R.;Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2999. (o) Sola, R.;Taillades, J.; Brugidou, J.; Commeyras, A. New J. Chem. 1989, 13, 881.(p) Tadros, Z.; Lagriffoul, P. H.; Mion, L.; Taillades, J.; Commeyras, A.

J. Chem. Soc., Chem. Commun. 1991, 1373. (q) Paventi, M.; Chubb, F. L.;Edward, J. T. Can. J. Chem. 1987, 65, 2114. (r) Paventi, M.; Edward, J. T.Can. J. Chem. 1987, 65, 282. For phosphate hydrolysis, see ref 4f.

(5) (a) Diederich, F.; Stang, P. J.Templated Organic Synthesis; Wiley-VCH: Chichester, U.K., 2000. (b) Bols, M.; Skrydstrup, T. Chem. Rev.1995, 95, 1253. (c) Fensterbank, L.; Malacria, M.; Sieburt, S. Synthesis1997, 813. (d) Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron1998, 54, 2289.

(6) (a) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; S�eguin, C.;Dimitrijevic, E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008,47, 1410. (b) Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M. E.;B�edard, A. C.; S�eguin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008,130, 17893. (c) Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.;B�edard, A. C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874.(d) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Whipp, C. J.; Gorelsky, S. I.;Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740. (e) Loiseau, F.;Clavette, C.; Raymond, M.; Roveda, J.-G.; Burrell, A.; Beauchemin,A. M. Chem. Commun. 2011, 47, 562.

(7) Such reactions are also often called reverse Cope cyclizations orreverse Cope eliminations in the literature. For an excellent review, see:Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.

(8) M€uller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.Chem. Rev. 2008, 108, 3795 and reviews cited therein.

(9) Nugent, T. Chiral Amine Synthesis; Wiley-VCH: Weinheim,Germany, 2010.

(10) Johns, A. M.; Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem.Soc. 2006, 128, 9306.

(11) (a) Gravestock, M. B.; Knight, D. W.; Thornton, S. R. J. Chem.Soc., Chem. Commun. 1993, 169. (b) Bell, K. E.; Coogan, M. P.;Gravestock, M. B.; Knight, D. W.; Thornton, S. R. Tetrahedron Lett.1997, 38, 8545. (c) Gravestock, M. B.; Knight, D. W.; Abdul Malik,K. M.; Thornton, S. R. J. Chem. Soc., Perkin Trans. 1 2000, 3292.

(12) For reviews of the use of carbonyl compounds as tetheringcatalysts for hydrolysis reactions, see refs 2a and 3a.

(13) (a) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.(b) List, B. Chem. Rev. 2007, 107, 5413. (c) MacMillan, D. W. C.Nature2008, 455, 304.

(14) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.1998, 37, 2580.

(15) For a review of reactions with chiral tethers, see: (a) Sugimura,T. Eur. J. Org. Chem. 2004, 1185. Typically, such chiral tethers are noteasily cleavable. For an exception, see: (b) Faure, S.; Blane, S. P.; Piva,O.; Pete, J. P. Tetrahedron Lett. 1997, 38, 1045. (c) Faure, S.; Piva-Le-Blanc, S.; Bertrand, C.; Pete, J. P.; Faure, R.; Piva, O. J. Org. Chem. 2002,67, 1061.

(16) (a) Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc.2009, 131, 5372. (b) Reznichenko, A. L.; Nguyen, H. N.; Hultzsch, K. C.Angew. Chem., Int. Ed. 2010, 49, 8984.

(17) For examples of enantioselective intermolecular hydroamina-tions in biased systems, see: (a) Dorta, R.; Egli, P.; Z€urcher, F.; Togni, A.J. Am. Chem. Soc. 1997, 119, 10857. (b) Kawatsura, M.; Hartwig, J. F.J. Am. Chem. Soc. 2000, 122, 9546. (c) L€ober, O.; Kawatsura, M.;Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. (d) Utsunomiya, M.;Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286. (e) Li, K.; Horton,P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250.(f) Hu, A.; Ogasawara, M.; Sakamoto, T.; Okada, A.; Nakajima, K.;Takahashi, T.; Lin, W. Adv. Synth. Catal. 2006, 348, 2051. (g) Zhou, J.;Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220.

(18) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000,442.

(19) For a leading review, see: Seebach, D.; Sting, A. R.; Hoffmann,M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708.